Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias

项目摘要 母项目的主要目标是开发WDR 5小分子降解剂作为抗癌药物。 治疗学WD 40重复结构域蛋白5（WDR 5），其功能为MLL组蛋白的必需亚基 甲基转移酶复合物是基因转录调控的关键，对维持肿瘤发生至关重要 在人类癌症中。WDR 5也与阿尔茨海默病（AD）有关，并且WDR 5抑制剂是有效的 改善AD小鼠的前额叶皮层突触功能和记忆相关行为。父项目 它并不专注于AD。本行政补充文件是对特别关注通知NOT-AG的回应- 22-025，针对非阿尔茨海默氏症的NIH赠款的阿尔茨海默氏症重点管理补充 疾病一些癌症患者还患有AD，这是一种毁灭性的神经退行性疾病，目前 没有有效的改善疾病的治疗方法。Synaptojanin 1（synj 1），主要的磷酸肌醇二磷酸 脑和突触中的降解酶在AD病理学中起关键作用。synj 1表达增加 和活动与AD的认知衰退和病理过程有关。Synj 1也是 与癌症有关它在各种癌症中过表达，synj 1的高表达与低表达相关。 癌症患者的预后。在我们的初步研究中，降低synj 1蛋白水平的化合物已经被发现。 发现了降低synj 1的先导化合物有效 在几种AD小鼠模型中。在这 行政补充，我们建议进行铅优化活动，以产生优化的synj 1- 降低化合物与 提高效力、选择性和脑渗透性。降低synj 1的化合物 在这种管理补充中产生的药物最终可以发展成为有效的治疗药物， 治疗AD，这也将使患有AD的癌症患者受益。这些降低synj 1的化合物 也可能是有用的抗癌疗法。

PROJECT SUMMARY The main objective of the parent project is to develop WDR5 small-molecule degraders as anticancer therapeutics. WD40 repeat domain protein 5 (WDR5), which functions an essential subunit of the MLL histone methyltransferase complex, is critical for gene transcription regulations and essential for sustaining oncogenesis in human cancers. WDR5 is also implicated in Alzheimer’s Disease (AD), and WDR5 inhibitors are efficacious in improving prefrontal cortex synaptic function and memory-related behaviors in AD mice. The parent project does not focus on AD. This administrative supplement is in response to the Notice of Special Interest NOT-AG- 22-025, Alzheimer’s-Focused Administrative Supplements for NIH Grants that are Not Focused on Alzheimer’s Disease. Some cancer patients also suffer from AD, a devastating neurodegenerative disorder, which currently has no effective disease-modifying therapeutics. Synaptojanin 1 (synj1), the main phosphoinositol bisphosphate degrading enzyme in the brain and synapses, plays a critical role in AD pathology. Increased synj1 expression and activities have been associated with cognitive decline and pathological processes of AD. Synj1 is also implicated in cancer. It is overexpressed in various cancers, and high expression of synj1 correlates with poor prognosis in cancer patients. In our preliminary studies, compounds that lower the synj1 protein level have been discovered. The lead synj1-lowering compounds were efficacious in several AD mouse models. In this administrative supplement, we propose to conduct a lead optimization campaign to generate optimized synj1- lowering compounds with improved potency, selectivity and brain penetration. The synj1-lowering compounds generated in this administrative supplement could ultimately be developed into effective therapeutics for the treatment of AD, which will also benefit cancer patients who suffer from AD. These synj1-lowering compounds could also be useful anticancer therapeutics.